PhD

Translational breast cancer program

NEW THERAPIES FOR BRAIN-METASTATIC HER2 BREAST CANCER

The HER2 subtype of breast cancer is associated with poor prognosis and high incidence of bone and brain metastasis. Despite the introduction of novel HER2-targeting therapies, resistance to treatment remains a major obstacle to effective treatment of advanced metastatic breast cancer.

Moreover, we are still unable to predict which HER2 patients likely to develop brain metastases. This project makes use of a new syngeneic mouse model of spontaneous HER2 breast cancer metastasis to identify a predictive gene signature allowing prospective identification of patients at high risk of developing brain metastases.

We will investigate mechanisms of resistance to HER2 inhibitors and test novel combination therapies targeting integrin and HER2 receptors in vitro and in vivo.

The project will make use of a broad variety of techniques including cell culture and in vitro inhibition assays, mRNA and protein expression analysis (FACS, western blot, immunohistochemistry, RNAseq), cell signaling and molecular biology techniques.

For further information about this PhD project or to apply, please email students@onjcri.org.au

Translational breast cancer program

Developing models to identify genes that regulate the spread of cancer to specific organs

Cancer & inflammation

ROLE OF DCLK1 AS A NOVEL DRIVER OF GASTRIC CANCER

Supervisors: Dr Michael Buchert, Prof Matthias Ernst

Gastric Cancer (GC) is among the most common cancers globally with a dismal 5-year survival of less than 28% and an urgent need for the identification of novel molecular targets and the development of associated therapies. The serine/threonine kinase doublecortin-like kinase 1 (DCLK1) has recently emerged as a novel potential driver of GC. Although DCLK1 gene amplification and other genetic alterations have been identified in human primary GC, and overall survival is reduced in GC patients with high DCLK1 expression, it remains unclear whether these alterations contribute to initiation or progression of disease. DCLK1 has also been suggested to serve as a marker for a rare population of intestinal stem cells, which becomes highly abundant in intestinal tumour stem cells (TSCs), but not in normal stem cells (NSCs). Targeted ablation of DCLK1-positive TSCs resulted in rapid regression of intestinal tumours without affecting homeostatic renewal of the normal intestine. Similar to these findings in the intestine our own preliminary results provide a compelling argument for a functional involvement of DCLK1-positive cells also in gastric tumourigenesis.

The goal of this PhD project is therefore to complement genetic, pharmacological tools as well as bioinformatics to assess the functional role of DCLK1-positive cells in the initiation, maintenance and progression of gastric tumours. Through this project the student will gain a comprehensive understanding of gastric epithelial (stem) cell biology and cancer biology and an extensive knowledge of preclinical models of cancer, molecular and cell biological techniques and bioinformatics.

A PhD scholarship is available to undertake this project beginning in mid-2016. For further information or to apply for this PhD position please email students@onjcri.org.au

Cancer & inflammation

Oncogenic transcription

UNDERSTANDING THE MOLECULAR BASIS FOR LOSS OF DIFFERENTIATION IN GASTROINTESTINAL CANCERS.

Supervisor: Prof John Mariadason

Cancers of the gastrointestinal epithelium, including cancers of the colon, stomach and biliary tract, account for almost 1.5 million deaths each year worldwide. A critical yet understudied feature of these cancers is the loss of cellular differentiation, which is associated with increased risk of metastasis and reduced response to chemotherapy. We have identified a number of transcription factors that are mutated or whose expression is lost in poorly differentiated cancers of the colon, stomach and biliary tract. This PhD project will directly determine the role of these transcription factors in regulating the differentiation status of these cancers, using cancer cell lines and genetic mouse models. In addition, the project will investigate new therapeutic strategies aimed at re-inducing differentiation of these tumours. Re-inducing tumour differentiation has the potential to improve outcomes for cancer patients by reducing metastasis and increasing chemosensitivity.

A PhD scholarship is available to undertake this project in early 2018.

Please send enquiries to john.mariadason@onjcri.org.au

Oncogenic transcription

Identifying the role of genes and proteins in the onset of gastrointestinal cancer

Cancer immunobiology

THE ROLE OF PREGNANCY-ASSOCIATED PLASMA PROTEIN A (PAPPA) IN MELANOMA DEVELOPMENT AND PROGRESSION

Supervisor: Prof Jonathon Cebon

We recently discovered that PAPPA is a highly expressed protein level in the majority of melanoma tumours, and that interference with its expression can reduce melanoma invasion in vitro and in vivo. Interestingly,PAPPA is highly expressed during pregnancy, and melanoma is the most commonly diagnosed cancer in pregnant women, and the most common malignancy encountered in women of child-bearing age (35%). Compared to the cancer rates in age-matched, non-pregnant women, the rate of melanoma in pregnant women was more than double (2.22; 95% CI 2.05–2.41) and there are various studies which report an aggressive course of melanoma during pregnancy. These data may provide a link between the observed severity of melanoma during pregnancy and high expression of PAPPA.

PAPPA and IGF-signalling

Dysregulated insulin growth factor (IGF)-signalling has been linked to various diseases, and a multitude of studies showed a relationship between the IGF pathways and cancer. Additionally, resistance against a variety of therapies against cancer has been reported to rely on IGF signalling. In melanoma, IGF/IGF-Receptor-1 (IGFR1) have been identified as potential therapeutic targets. Multiple therapies aiming to block this pathway have been trialled in clinic; but unfortunately, these strategies did not translate into significant benefits for patients in clinical trials. This was largely hampered by severe side-effects attributed to the global role of IGF signalling in normal physiology and the dual specificity of the therapeutics to IGFR and insulin receptors. IGF circulates in serum bound to IGF-binding proteins (IGFBP) in an inactive form and can be locally released by proteolytic cleavage of the complex. The main protease for this is the pregnancy-associated plasma protein A (PAPPA), which is associated with cell surface heparan sulfate proteoglycans and remains an active protease when cell-bound. Hereby, PAPPA can spatially regulate IGF signalling.

The aims of this PhD project are to:

characterize the biological activities of PAPPA in melanoma cells and the functional changes after interference with the PAPPA/IGF axis.